Somatostatin-induced paradoxical increase in intracellular Ca²⁺ concentration and insulin release in the presence of arginine vasopressin in clonal HIT-T15 β-cells

Somatostatin, a hormone that signals via G_i/G_o, usually inhibits increases in intracellular calcium concentration ([Ca²⁺]_i) and insulin release from β-cells. We have found that in the presence of arginine vasopressin (AVP), which signals via G_q, somatostatin increased [Ca²⁺]_i, leading to insulin release in HIT-T15 cells. The increase in [Ca²⁺]_i by somatostatin was observed even after 60 min of AVP treatment. Somatostatin alone failed to increase [Ca²⁺]_i and insulin release. Somatostatin induced changes in [Ca²⁺]_i in a biphasic pattern, characterized by a sharp and transient increase followed by a rapid decline to sub-basal levels. Pretreatment with pertussis toxin, which inactivates G_i/G_o, abolished the effects of somatostatin. U-73122, an inhibitor of phospholipase C, antagonized the somatostatin-induced increase in [Ca²⁺]_i. In Ca²⁺-free medium, somatostatin still increased [Ca²⁺]_i. Depletion of intracellular Ca²⁺ stores with thapsigargin, a microsomal Ca²⁺-ATPase inhibitor, abolished somatostatin's effect. In the presence of bradykinin, another G_q-coupled receptor agonist, somatostatin also increased [Ca²⁺]_i, but not in the presence of isoproterenol (a G_s-coupled receptor agonist) or medetomidine (a G_i/G_o-coupled receptor agonist). Our findings suggest that somatostatin signals through G_i/G_o, and involves phospholipase C and Ca²⁺ release from the endoplasmic reticulum. The increase in [Ca²⁺]_i by somatostatin leads to insulin release. This cross-talk is specific to G_q and G_i/G_o, and is not limited to the AVP and somatostatin receptors.